1-Aminonaphthyridines

ABSTRACT

This invention relates to 1-amino naphthyridines prepared by a base-catalyzed condensation while in an aprotic solvent. In this condensation an o-alkyl aryl nitrile may be reacted either with the same or different o-alkyl aryl nitrile or with another nitrile. The 1-amino naphthyridines are useful as antifungal and antibacterial agents.

This application is a division of application Ser. No. 631,010 filedNov. 12, 1975, and now U.S. Pat. No. 4,017,500, which in turn is adivisional of our copending application, Ser. No. 379,525, filed July16, 1973, and now is U.S. Pat. No. 3,928,367, which in turn, is acontinuation-in-part of application Ser. No. 119,377, filed Feb. 26,1971, now abandoned, which application in turn, is acontinuation-in-part application of our copending application, Ser. No.816,075, filed Apr. 14, 1969, now abandoned.

This invention relates to novel compositions of matter which maygenerically be described as 1-amino 3-substituted naphthyridines, toprocesses for their preparation and to their applied use characteristicsas antibacterial and antifungal agents.

More particularly, this invention, in its composition of matter aspect,relates to 1-amino-2,5-naphthyridines, to 1-amino-2,6-naphthyridines,1-amino-2,7-naphthyridines, to 8-amino-1,7-naphthyridines, each of saidgroups of naphthyrdidines being further substituted with suchsubstituents as lower alkyl, phenyl, benzyl, phenethyl, pyridyl,thienyl, furyl, pyrazinyl, and pyrimidyl radicals.

In its process aspects this invention relates to the base-catalyzedcondensation of an ortho-alkyl aryl nitrile either with itself or withanother appropriate nitrile, said condensation taking place in anaprotic solvent.

In another of its process aspects, this invention relates to theapplication of the compositions of matter of this invention asantibacterial agents, said agents being utilized preferably in the formof the pharmaceutical formulations prepared consistent with skills wellknown and practiced by pharmaceutical artisans.

In another of its process aspects, this invention relates to theapplication of the compositions of this invention as antifungal agents,said agents being utilized preferably in the form of pharmaceuticalformulations prepared consistent with skills well known bypharmaceutical artisans.

The compositions of matter of this invention may generically be depictedas naphthyridines having the structural formula: ##STR1## wherein R₁represents lower alkyl, phenyl, benzyl, phenethyl, thienyl, furyl,pyrazinyl, pyrimidyl, or pyridyl, R₂ represents hydrogen, lower alkyl,phenyl, benzyl, phenethyl and pyridyl, and B, together with the carbonatoms to which it is attached, is a pyrido moiety.

More conveniently, the naphthyridines may also be depicted by thefollowing structural formulae: ##STR2## wherein R₁ and R₂ are as definedfor I, said structures Ia, Ib, Ic, and Id being8-amino-1,7-naphthyridines, 1-amino-2,7-naphthyridines,1-amino-2,6-naphthyridines, and 1-amino-2,5-naphthyridines,respectively.

Here, and elsewhere through this specification it will be understoodthat the phenyl, benzyl, thienyl, furyl, phenethyl, pyrazinyl,pyrimidinyl and pyridyl substituents, as well as the pyrido moieties ofthe naphthyridine ring structures, can bear such other substituents aswould occur to a skilled organic chemist. Solely for illustration andwithout limitation, such substituents include lower alkyl, lower alkoxy,halo (chloro, bromo, iodo) nitro, lower alkylmercapto, trifluoromethyland di(loweralkyl)amino and the like.

As used throughout this specification, the term "lower alkyl" meansalkyl radicals having from one to six carbon atoms which can be arrangedas straight or branched chains, and among which are, for purposes ofillustration but without limiting the generality of the foregoing,methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl and n-hexyl.

The process aspect of this invention is carried out by condensing theappropriate reactants in the presence of a base which is in an atropicnon-reactive solvent at temperatures of about -60° C. to about 80° C.More specifically, the process for preparing the compounds of thisinvention is essentially comprised of the condensation of an ortho-alkylarylnitrile either with the same or different ortho-alkyl arylnitrile orwith another type organic nitrile. In effecting the condensation thereactants are brought into contact with each other in the presence of abase; preferably, the reaction taking place in a solvent. In general,any atropic non-reacting solvent is suitable and such solvents includehydrocarbons, halohydrocarbons, tertiary amines, ammonia, ethers,tertiary amides, nitriles and the like, satisfying the requirements thatthey be liquid at reaction temperatures. Preferred solvents aredimethylformamide, dimethylsulfoxide, tetramethylurea,hexamethylphosphoramide, dioxane, tetrahydrofuran, dimethoxyethane,ether liquid ammonia, benzene, toluene and xylene. The bases generallyfound suitable for this reaction are the commonly used strong bases foralkylation reactions and include, potassium, t-butoxide, sodiumt-amylate, sodium 2-methyl-2-butoxide, alkali metal amides such assodium amide, potassium amide, lithium diethylamide, lithiumdiisopropylamide, sodium hydride, lithium hydride, triphenylmethyllithium, triphenylmethyl sodium, naphthalene sodium and triphenylmethylpotassium. In general, the reactants are stirred together attemperatures in the range of about -60° to about 80° C., thistemperature, of course, being dependent upon the solvent and speed ofreaction desired. Preferably the reaction temperature is about 0° C.,although more specific reactant/solvent/temperature/combination factorsare described in the working examples set forth hereinbelow.

The nature of the general chemical reaction involved as well as of thegeneral nature of the compounds formed may be illustrated as follows:##STR3## wherein B, R₁ and R₂ are as previously defined.

From the foregoing reaction scheme it becomes obvious that the secondcyano molecule (IV) participating in the reaction (i.e. R₁ CN) caneither be identical with the ortho-alkyl aryl nitrol (II) molecule ordifferent from it. In the first case the general structure of theproduct will be as follows: ##STR4## wherein R₁, R₂ and B are aspreviously described and A is a pyridyl radical. In the second situationwherein the reactants are different, i.e., II and R₁ CN are not thesame, the general structure of the reaction product is as given forformula I. In the latter situation condensation between two molecules ofthe first component (II) can also take place as a side reaction. In suchsituations separation of the desired product may be accomplished bystandard techniques such as fractional crystallization and columnchromatographic techniques.

It is also obvious from the reaction scheme that when differentortho-alkyl aryl nitriles are condensed, four different products mayresult therefrom. Such products may be represented as follows: ##STR5##wherein the ##STR6## moieties represent different pyrido formations andR₂ is as defined in formula I. Again, in such situations separation ofthe desired product may be accomplished by standard techniques such asfractional crystallization and column chromatographic techniques.Representative of the organic nitriles (IV) suitable for reaction withthe o-alkyl aryl nitriles of formula II are such compounds as2-cyanopyridine, 3-cyanopyridine, 4-cyanopyridine, benzonitrile, o, mand p methoxy benzonitrile, 2,3- 2,6- 3,4- and 3,5-dimethoxybenzonitrile, 3,4-methylenedioxyphenyl acetonitrile, o, m and pchlorobenzonitrile, trifluoromethyl benzonitrile, 1- and2-naphthonitrile, benzylcyanide, o, m and p chlorobenzyl cyanide, o, mand p methylbenzyl cyanide, homoveratro nitrile, 4-methoxybenzylcyanide, 2-cyano thiophene 2- and 3-thiophene acetonitrile,2-cyanofurane, cyclobutyl cyanide, cyclopentyl cyanide, cyclohexylcyanide and the like.

The following examples will further illustrate the process aspects forproducing the tangible embodiments of the compounds of this invention.

EXAMPLE 1 Preparation of 1-amino-2,5-naphthyridines1-Amino-3(2-methyl-3-pyridyl)-2,5-naphthyridine

To 5.9 of 3-cyano-2-methylpyridine dissolved in 30 ml. ofdimethylformamide, gradually add 6.7 g. of potassium t-butoxide at about5° C. Maintain the mixture at 5° C. for 4-6 hours and quench thereaction in ice water. Collect the crystalline precipitate andrecrystallize from toluene to yield1-amino-3(2-methyl-3-pyridyl)-2,5-naphthyridine.

In a similar manner by substituting the 3-cyano-2-methylpyridine withequivalent quantities of 3-cyano-2-ethylpyridine,3-cyano-2-benzylpyridine, 3-cyano-2-phenethylpyridine and3-cyano-2-phenylpropylpyridine and by substantially following theprocedure of this example there is produced1-amino-3(2-ethyl-3-pyridyl)-4-methyl-2,5-naphthyridine;1-amino-3-(2-benzyl-3-pyridyl)-4-phenyl-2,5-naphthyridine;1-amino-3-(2-phenethyl-3-pyridyl)-4-benzyl-2,5-naphthyridine;1-amino-3-(2-phenylpropyl-3-pyridyl)-4-phenethyl-2,5-naphthyridine,respectively. Similarly, in those instances wherein it is desired toproduce those compounds bearing substituents on the pyridyl, phenyl andbenzyl moieties of the foregoing then, as expected, the appropriatelysubstituted starting reactants are then similarly reacted.

EXAMPLE II 1-Amino-3-methyl-2,5-naphthyridine

To 6.7 g. of potassium-t-butoxide in dimethylformamide at 0°-5° C. add,in a portionwise fashion, 5.9 g. of 3-cyano-2-methylpyridine and stirthe reaction mixture for 1 hour. Add in a portionwise fashion, 10.2 g.of acetonitrile and stir the reaction mixture at 0°-5° C. for 48 hours.Quench the reaction in ice water, filter the precipitate andrecrystallize the desired 1-amino-3-methyl-2,5-naphthyridine fromtoluene.

In a similar manner by substituting the acetonitrile of the foregoingreaction with equivalent quantities of benzonitrile, benzylcyanide,phenpropionitrile, propionitrile, 2-cyanopyridine, 3-cyanopyridine,4-cyanopyridine, 2-methoxybenzonitrile, 3-methoxybenzonitrile,4-methoxybenzonitrile, 2,3-dimethoxybenzonitrile,2,6-dimethoxybenzonitrile, 3,4-methylenedioxybenzonitrile,2-chlorobenzonitrile, 3-chlorobenzonitrile, 4-chlorobenzonitrile,2-trifluorobenzonitrile, 3-trifluorobenzonitrile,4-trifluorobenzonitrile, 1-naphthonitrile, 2-naphthonitrile,2-chlorobenzylcyanide, 3-chlorobenzylcyanide, 4-chlorobenzylcyanide,2-methylbenzylcyanide, 3-methylbenzylcyanide and 4-methylbenzylcyanide,4-methoxybenzylcyanide, 2-cyanothiophene, 2-thiopheneacetonitrile,3-thiopheneacetonitrile, 2-cyanofuran, cyclobutylcyanide,cyclopentylcyanide, cyclohexylcyanide, 2-cyanopyrimidine,5-cyanopyrimidine, 2-cyanopyrazine and by substantially following theforegoing reaction procedure there is produced1-amino-3-phenyl-2,5-naphthyridine, 1-amino-3-benzyl-2,5-naphthyridine,1-amino-3-phenethyl-2,5-naphthyridine,1-amino-3-ethyl-2,5-naphthyridine,1-amino-3-(2-pyridyl)-2,5-naphthyridine,1-amino-3-(3-pyridyl)-2,5-naphthyridine,1-amino-3-(4-pyridyl)-2,5-naphthyridine,1-amino-3-(2-methoxyphenyl)-2,5-naphthyridine,1-amino-3-(3-methoxyphenyl)-2,5-naphthyridine,1-amino-3-(4-methoxyphenyl)-2,5-naphthyridine,1-amino-3-(2,3-dimethoxyphenyl)-2,5-naphthyridine,1-amino-3-(2,6-dimethoxyphenyl)-2,5-naphthyridine,1-amino-3-(3,4-methylenedioxyphenyl)-2,5-naphthyridine,1-amino-3-(2-chlorophenyl)-2,5-naphthyridine,1-amino-3-(3-chlorphenyl)-2,5-naphthyridine,1-amino-3-(4-chlorphenyl)-2,5-naphthyridine,1-amino-3-(2-trifluoromethylphenyl)-2,5-naphthyridine,1-amino-3-(3-trifluoromethylphenyl)-2,5-naphthyridine,1-amino-3-(4-trifluoromethylphenyl)-2,5-naphthyridine,1-amino-3-(α-naphthyl)-2,5-naphthyridine,1-amino-3-(β-naphthyl)-2,5-naphthyridine,1-amino-3-(2-chlorobenzyl)-2,5-naphthyridine,1-amino-3-(3-chlorobenzyl)-2,5-naphthyridine,1-amino-3-(4-chlorobenzyl)-2,5-naphthyridine,1-amino-3-(2-methylbenzyl)-2,5-naphthyridine,1-amino-3-(3-methylbenzyl)-2,5-naphthyridine,1-amino-3-(4-methylbenzyl)-2,5-naphthyridine,1-amino-3-(4-methoxybenzyl)-2,5-naphthyridine,1-amino-3-(2-thienyl)-2,5-naphthyridine,1-amino-3-(2-thienylmethyl)-2,5-naphthyridine,1-amino-3-(3-thienylmethyl)-2,5-naphthyridine,1-amino-3-(2-furyl)-2,5-naphthyridine,1-amino-3-cyclobutyl-2,5-naphthyridine,1-amino-3-cyclopentyl-2,5-naphthyridine,1-amino-3-cyclohexyl-2,5-naphthyridine,1-amino-3-(2-pyrimidinyl)-2,5-naphthyridine,1-amino-3-(3-pyrimidinyl)-2,5-naphthyridine,1-amino-3-(2-pyrazinyl)-2,5-naphthyridine.

Similarly, by substituting the 3-cyano-2-methylpyridine reactant withequivalent quantities of 3-cyano-2-ethylpyridine,3-cyano-2-benzylpyridine, 3-cyano-2-phenethylpyridine and bysubstantially following the foregoing reaction procedure there isproduced 1-amino-3,4-dimethyl-2,5-naphthyridine,1-amino-3-methyl-4-phenyl-2,5-naphthyridine,1-amino-3-methyl-4-benzyl-2,5-naphthyridine, respectively. Similarly, ineach of those reactions wherein the 3-cyano-2-methylpyridine has beensubstituted with another 3-cyano-2-substituted pyridine the acetonitrilereactant may also be substituted with the aforementioned nitriles and bysubstantially following the procedure described in the example, there isproduced the appropriate 1-amino-3- and 4-substituted,2,5-naphthyridines.

EXAMPLE III Preparation of 1-amino-2,6-naphthyridines1-Amino-3-(3-methyl-4-pyridyl)-2,6-naphthyridine

To 5.9 g. of 4-cyano-3-methylpyridine dissolved in 30 ml. ofdimethylformamide, generally add 6.7 g. of potassium t-butoxide at about5° C. Maintain the mixture of 5° C. for 4-6 hours and quench thereaction in ice water. Collect the crystalline precipitate andrecrystallize from toluene to yield1-amino-3-(3-methyl-4-pyridyl)-2,6-naphthyridine.

In a similar manner by substituting the 4-cyano-3-methylpyridine withequivalent quantities of 4-cyano-3-ethylpyridine,4-cyano-3-benzylpyridine, 4-cyano-3-phenethylpyridine and4-cyano-3-phenylpropylpyridine and by substantially following theprocedure of this example there is produced1-amino-3-(3-ethyl-4-pyridyl)-4-methyl-2,6-naphthyridine,1-amino-3-(3-benzyl-4-pyridyl)-4-phenyl-2,6-naphthyridine,1-amino-3-(3-phenethyl-4-pyridyl)-4-benzyl-2,6-naphthyridine,1-amino-3-(3-phenylpropyl-4-pyridyl)-4-phenethyl-2,6-naphthyridine,respectively. Similarly, in those instances wherein it is desired toproduce those compounds bearing substituents on the pyridyl, phenyl orbenzyl moieties of the foregoing then, as expected, the appropriatelysubstituted starting reactants are then reacted according to theprocedure set forth in this example.

EXAMPLE IV 1-Amino-3-methyl-2,6-naphthyridine

To 6.7 g. of potassium t-butoxide in dimethylformamide at 0°-5° C. add,in a portionwise fashion, 5.9 g. of 4-cyano-3-methylpyridine and stirthe reaction mixture for 1 hour. Add, in a portionwise fashion, 10.2 g.of acetonitrile and stir the reaction mixture at 0°-5° C. for 48 hours.Quench the reaction in ice water, filter the precipitate andrecrystallize the desired 1-amino-3-methyl-2,6-naphthyridine.

In a similar manner by substituting the acetonitrile of the foregoingreaction with equivalent quantities of benzonitrile, benzylcyanide,phenpropionitrile, propionitrile, 2-cyanopyridine, 3-cyanopyridine,4-cyanopyridine, 2-methoxybenzonitrile, 3-methoxybenzonitrile,4-methoxybenzonitrile, 2,3-dimethoxybenzonitrile,2,6-dimethoxybenzonitrile, 3,4-methylenedioxybenzonitrile,2-chlorobenzonitrile, 3-chlorobenzonitrile, 4-chlorobenzonitrile,2-trifluorobenzonitrile, 3-trifluorobenzonitrile,4-trifluorobenzonitrile, 1-naphthonitrile, 2-naphthonitrile,2-chlorobenzylcyanide, 3-chlorobenzylcyanide, 4-chlorobenzylcyanide,2-methylbenzylcyanide, 3-methylbenzylcyanide, and 4-methylbenzylcyanide,4-methoxybenzylcyanide, 2-cyanothiophene, 2-thiopheneacetonitrile,3-thiopheneacetonitrile, 2-cyanofuran, cyclobutylcyanide,cyclopentylcyanide, cyclohexylcyanide, 2-cyanopyrimidine,5-cyanopyrimidine, 2-cyanopyrazine and by substantially following theforegoing reaction procedure there is produced1-amino-3-phenyl-2,6-naphthyridine, 1-amino-3-benzyl-2,6-naphthyridine,1-amino-3-phenethyl-2,6-naphthyridine,1-amino-3-ethyl-2,6-naphthyridine,1-amino-3-(2-pyridyl)-2,6-naphthyridine,1-amino-3-(3-pyridyl)-2,6-naphthyridine,1-amino-3-(4-pyridyl)-2,6-naphthyridine,1-amino-3-(2-methoxyphenyl)-2,6-naphthyridine,1-amino-3-(3-methoxyphenyl)-2,6-naphthyridine,1-amino-3-(4-methoxyphenyl)-2,6-naphthyridine,1-amino-3-(2,3-dimethoxyphenyl)-2,6-naphthyridine,1-amino-3-(2,6-dimethoxyphenyl)-2,6-naphthyridine,1-amino-3-(3,4-methylenedioxyphenyl)-2,6-naphthyridine,1-amino-3-(2-chlorphenyl)-2,6-naphthyridine,1-amino-3-(3-chlorphenyl)-2,6-naphthyridine,1-amino-3-(4-chlorphenyl)-2,6-naphthyridine,1-amino-3-(2-trifluoromethylphenyl)-2,6-naphthyridine,1-amino-3-(3-trifluoromethylphenyl)-2,6-naphthyridine,1-amino-3-(4-trifluoromethylphenyl)-2,6-naphthyridine,1-amino-3-(α-naphthyl)-2,6-naphthyridine,1-amino-3-(β-naphthyl)-2,6-naphthyridine,1-amino-3-(2-chlorobenzyl)-2,6-naphthyridine,1-amino-3-(3-chlorobenzyl)-2,6-naphthyridine,1-amino-3-(4-chlorobenzyl)-2,6-naphthyridine,1-amino-3-(2-methylbenzyl)-2,6-naphthyridine,1-amino-3-(3-methylbenzyl)-2,6-naphthyridine,1-amino-3-(4-methylbenzyl)-2,6-naphthyridine,1-amino-3-(4-methoxybenzyl)-2,6-naphthyridine,1-amino-3-(2-thienyl)-2,5-naphthyridine,1-amino-3-(2-thienylmethyl)-2,6-naphthyridine,1-amino-3-(3-thienylmethyl)-2,6-naphthyridine,1-amino-3-(2-furyl)-2,6-naphthyridine,1-amino-3-cyclobutyl-2,6-naphthyridine,1-amino-3-cyclopentyl-2,6-naphthyridine,1-amino-3-cyclohexyl-2,6-naphthyridine,1-amino-3-(2-pyrimidinyl)-2,6-naphthyridine,1-amino-3-(3-pyrimidinyl)-2,6-naphthyridine,1-amino-3-(2-pyrazinyl)-2,6-naphthyridine.

Also by substituting the 4-cyano-3-methylpyridine with equivalentquantities of 4-cyano-3-ethylpyridine, 4-cyano-3-benzylpyridine,4-cyano-3-propylpyridine, 4-cyano-3-phenethylpyridine,4-cyano-3-phenylpropylpyridine and by substantially following theforegoing reaction procedure there is produced1-amino-3,4-dimethyl-2,6-naphthyridine,1-amino-3-methyl-4-phenyl-2,6-naphthyridine,1-amino-3-methyl-4-benzyl-2,6-naphthyridine,1-amino-3-methyl-4-phenethyl-2,6-naphthyridine, respectively. Also ineach of those reactions wherein the 4-cyano-3-methylpyridine has beensubstituted with another 4-cyano-3-substituted pyridine, theacetonitrile reactant may also be substituted with the aforementionednitriles and by substantially following the procedure described in thisexample there is produced the appropriately 1-amino-3- and 4-substituted2,6-naphthyridines.

EXAMPLE V Preparation of 1-amino-2,7-naphthyridines1-Amino-3-(4-methyl-3-pyridyl)-2,7-naphthyridines

To 3 g. of 3-cyano-4-methylpyridine dissolved in 30 ml. ofdimethylformamide, gradually add 3.4 g. of potassium t-butoxide at about5° C. over a period of 20 minutes. Maintain the reaction at 5° C. andthen at 20°-25° C. for another 12 hours. Quench the reaction in icewater, collect the precipitate and recrystallize from ethanol-hexane toyield 1-amino-3-(4-methyl-3-pyridyl)-2,7-naphthyridine, m.p. 280°-282°C.

In a similar manner by substituting the 3-cyano-4-methylpyridine withequivalent quantities of 3-cyano-4-ethylpyridine,3-cyano-4-benzylpyridine, 3-cyano-4-phenethylpyridine and3-cyano-4-phenylpropylpyridine and by substantially following theprocedure of this example there is produced1-amino-3-(4-ethyl-3-pyridyl)-4-methyl-2,7-naphthyridine;1-amino-3-(4-phenethyl-3-pyridyl)-4-phenyl-2,7-naphthyridine;1-amino-3-(4-phenethyl-3-pyridyl)-4-benzyl-2,7-naphthyridine;1-amino-3-(4-phenylpropyl-3-pyridyl)-4-phenethyl-2,7-naphthyridine,respectively. Similarly, in those instances wherein it is desired toproduce those compounds bearing substituents on the pyrido, pyridyl,phenyl and benzyl moieties of the foregoing then, as expected, theappropriately substituted starting reactants are then similarly reacted.

EXAMPLE VI 1-Amino-3-methyl-2,7-naphthyridine

To 6.7 g. of potassium t-butoxide in dimethylformamide at 0°-5° C. add,in a portionwise fashion, 5.9 g. of 3-cyano-4-methylpyridine and stirthe reaction mixture for 1 hour. Add, in a portionwise fashion, 10.2 g.of acetonitrile and stir the reaction mixture at 0°-5° C. for 48 hours.Quench the reaction in ice water, filter the precipitate andrecrystallize the desired 1-amino-3-methyl-2,7-naphthyridine fromtoluene.

In a similar manner by substituting the acetonitrile of the foregoingreaction with equivalent quantities of benzonitrile, benzylcyanide,phenpropionitrile, propionitrile, 2-cyanopyridine, 3-cyanopyridine,4-cyanopyridine, 2-methoxybenzonitrile, 3-methoxybenzonitrile,4-methoxybenzonitrile, 2,3-dimethoxybenzonitrile,2,6-dimethoxybenzonitrile, 3,4-methylenedioxybenzonitrile,2-chlorobenzonitrile, 3-chlorobenzonitrile, 4-chlorobenzonitrile,2-trifluorobenzonitrile, 3-trifluorobenzonitrile,4-trifluorobenzonitrile, 1-naphthonitrile, 2-naphthonitrile,2-chlorobenzylcyanide, 3-chlorobenzylcyanide, 4-chlorobenzylcyanide,2-methylbenzylcyanide, 3-methylbenzylcyanide and 4-methylbenzylcyanide,4-methoxybenzylcyanide, 2-cyanothiophene, 2-thiopheneacetonitrile,3-thiopheneacetonitrile, 2-cyanofuran, cyclobutylcyanide,cyclopentylcyanide, cyclohexylcyanide, 2-cyanopyrimidine,5-cyanopyrimidine, 2-cyanopyrazine and by substantially following theforegoing reaction procedure there is produced1-amino-3-phenyl-2,7-naphthyridine, 1-amino-3-benzyl-2,7-naphthyridine,1-amino-3-phenethyl-2,7-naphthyridine,1-amino-3-ethyl-2,7-naphthyridine,1-amino-3-(2-pyridyl)-2,7-naphthyridine,1-amino-3-(3-pyridyl)-2,7-naphthyridine,1-amino-3-(4-pyridyl)-2,7-naphthyridine,1-amino-3-(2-methoxyphenyl)-2,7-naphthyridine,1-amino-3-(3-methoxyphenyl)-2,7-naphthyridine,1-amino-3-(4-methoxyphenyl)-2,7-naphthyridine,1-amino-3-(2,3-dimethoxyphenyl)-2,7-naphthyridine,1-amino-3-(2,6-dimethoxyphenyl)-2,7-naphthyridine,1-amino-3-(3,4-methylenedioxyphenyl)-2,7-naphthyridine,1-amino-3-(2-chlorophenyl)-2,7-naphthyridine,1-amino-3-(3-chlorophenyl)-2,7-naphthyridine,1-amino-3-(4-chlorophenyl)-2,7-naphthyridine,1-amino-3-(2-trifluoromethylphenyl)-2,7-naphthyridine,1-amino-3-(3-trifluoromethylphenyl)-2,7-naphthyridine,1-amino-3-(4-trifluoromethylphenyl)-2,7-naphthyridine,1-amino-3-(α-naphthyl)-2,7-naphthyridine,1-amino-3-(β-naphthyl)-2,7-naphthyridine,1-amino-3-(2-chlorobenzyl)-2,7-naphthyridine,1-amino-3-(3-chlorobenzyl)-2,7-naphthyridine,1-amino-3-(4-chlorobenzyl)-2,7-naphthyridine,1-amino-3-(2-methylbenzyl)-2,7-naphthyridine,1-amino-3-(3-methylbenzyl)-2,7-naphthyridine,1-amino-3-(4-methylbenzyl)-2,7-naphthyridine,1-amino-3-(4-methoxybenzyl)-2,7-naphthyridine,1-amino-3-(2-thienyl)-2,7-naphthyridine,1-amino-3-(2-thienylmethyl)-2,7-naphthyridine,1-amino-3-(3-thienylmethyl)-2,7-naphthyridine,1-amino-3-(2-furyl)-2,7-naphthyridine,1-amino-3-cyclobutyl-2,7-naphthyridine,1-amino-3-cyclopentyl-2,7-naphthyridine,1-amino-3-cyclohexyl-2,7-naphthyridine,1-amino-3-(2-pyrimidinyl)-2,7-naphthyridine,1-amino-3-(3-pyrimidinyl)-2,7-naphthyridine,1-amino-3-(2-pyrazinyl)-2,7-naphthyridine.

Similarly, by substituting the 3-cyano-4-methylpyridine, reactant withequivalent quantities of 3-cyano-4-ethylpyridine,3-cyano-4-benzylpyridine, 3-cyano-4-phenethylpyridine and bysubstantially following the foregoing reaction procedure there isproduced 1-amino-3,4-dimethyl-2,7-naphthyridine,1-amino-3-methyl-4-phenyl-2,7-naphthyridine,1-amino-3-methyl-4-benzyl-2,7-naphthyridine, respectively. Similarly, ineach of those reactions wherein the 3-cyano-4-methylpyridine has beensubstituted with another 3-cyano-4-substituted pyridine the acetonitrilereactant may also be substituted with the aforementioned nitriles and bysubstantially following the procedure described in the example, there isproduced the appropriate 1-amino-3- and 4-substituted 2,5-naphthyridine.

EXAMPLE VII Preparation of 1,7-naphthyridine8-Amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine

To 5.9 g. of 2-cyano-3-methylpyridine dissolved in 30 mls. ofdimethylformamide gradually (20 minutes) add 6.7 g. of potassiumt-butoxide at about 5° C. Maintain the reaction mixture at 5° C. for 4-6hours and quench the reaction mixture in ice water. Collect thecrystalline precipitate and recrystallize from toluene obtaining 3.7 g.of 8-amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine, m.p. 170°-171° C.

EXAMPLE VIII 8-Amino-2-(3-ethyl-2-pyridyl)-3-methyl-1,7-naphthyridine

To 6.3 g. of 2-cyano-3-ethylpyridine (prepared from 3-ethylpyridine bythe method described for the preparation of 2-cyano-6-methylpyridinefrom 2-methylpyridine in Organic Synthesis, Vol. 42, p. 30. The2-cyano-3-ethylpyridine is separated from the 6-cyano and 4-cyanoisomers by fractional crystallization from 2B-ethanol or isopropanol)dissolved in 30 mls. of dimethylformamide, gradually add 6.7 g. ofpotassium t-butoxide at about 5° C. over a period of 20 minutes.Maintain the reaction mixture at 5° C. for another 4-6 hours and thenquench the reaction mixture in ice water. Collect the crystallineprecipitate and recrystallize from toluene to yield8-amino-2-(3-ethyl-2-pyridyl)-3-methyl-1,7-naphthyridine.

In a similar manner by substituting the 2-cyano-3-methyl-pyridine withequivalent quantities of 2-cyano-3-benzylpyridine,2-cyano-3-phenethylpyridine and 2-cyano-3-phenylpropylpyridine and bysubstantially following the procedure of this example there is produced8-amino-2-(3-benzyl-2-pyridyl)-3-phenyl-1,7-naphthyridine,8-amino-2-(3-phenethyl-2-pyridyl)-3-benzyl-1,7-naphthyridine,8-amino-2-(3-phenylpropyl-2-pyridyl)-3-phenethyl-1,7-naphthyridine,respectively. Similarly, in those instances wherein it is desired toproduce those compounds bearing substituents on the pyridyl, phenyl andbenzyl moieties of the foregoing then, as expected, the appropriatelysubstituted starting reactants are then similarly reacted.

EXAMPLE IX 8-Amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine

To a suspension of sodamide (prepared from 0.23 g. of sodium) in 200 ml.of liquid ammonia gradually add 5.9 g. of 2-cyano-3-methylpyridine.Agitate the reaction mixture for 4 hours, add 6 g. of ammonium chlorideand, using steam bath temperatures, evaporate off the ammonia. Addsufficient water to dissolve the inorganic material and filter theremaining precipitate which is recrystallized from toluene to give8-amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine, m.p. 170°-171° C.

EXAMPLE X 8-Amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine

To a suspension in ether of lithium diisopropylamide (prepared from 0.2moles of lithium, 0.1 moles of brombenzene and 0.1 moles ofdiisopropylamine) add, in a dropwise fashion, at 25°-35° C., an ethersolution containing 0.1 mole of 2-cyano-3-methylpyridine. Reflux thereaction mixture for 7 hours, and pour the resulting mixture into icewater. Filter the precipitated8-amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine and recrystallize theproduct from toluene.

EXAMPLE XI 8-Amino-2-methyl-1,7-naphthyridine

To 6.7 g. of potassium t-butoxide in dimethylformamide at 0.5° C. add,in a portionwise fashion, 5.9 g. of 2-cyano-3-methylpyridine and stirthe reaction mixture for 1 hour. Add, in a portionwise fashion, 10.2 g.of acetonitrile and stir the reaction mixture at 0.5° C. for 48 hours.Quench the reaction in ice water, filter the precipitate andrecrystallize the desired 8-amino-2-methyl-1,7-naphthyridine fromtoluene.

In a similar manner by substituting the acetonitrile of the foregoingreaction with equivalent quantities of benzonitrile, benzylcyanide,phenpropionitrile, propionitrile, 2-cyanopyridine, 3-cyanopyridine,4-cyanopyridine, 2-methoxybenzonitrile, 3-methoxybenzonitrile,4-methoxybenzonitrile, 2,3-dimethoxybenzonitrile,2,6-dimethoxybenzonitrile, 3,4-methylenedioxybenzonitrile,2-chlorobenzonitrile, 3-chlorobenzonitrile, 4-chlorobenzonitrile,2-trifluorobenzonitrile, 3-trifluorobenzonitrile,4-trifluorobenzonitrile, 1-naphtonitrile, 2-naphtonitrile,2-chlorobenzylcyanide, 3-chlorobenzylcyanide, 4-chlorobenzylcyanide,2-methylbenzylcyanide, 3-methylbenzylcyanide and 4-methylbenzylcyanide,4-methoxybenzylcyanide, 2-cyanothiophene, 2-thiopheneacetonitrile,3-thiopheneacetonitrile, 2-cyanofuran, cyclobutylcyanide,cyclopentylcyanide, cyclohexylcyanide, 2-cyanopyrimidine,5-cyanopyrimidine, 2-cyanopyrazine and by substantially following theforegoing reaction procedure there is produced8-amino-2-phenyl-1,7-naphthyridine, 8-amino-2-benzyl-1,7-naphthyridine,8-amino-2-phenethyl-1,7-naphthyridine,8-amino-2-ethyl-1,7-naphthyridine,8-amino-2-(2-pyridyl)-1,7-naphthyridine,8-amino-2-(3-pyridyl)-1,7-naphthyridine,8-amino-2-(4-pyridyl)-1,7-naphthyridine,8-amino-2-(2-methoxyphenyl)-1,7-naphthyridine,8-amino-2-(3-methoxyphenyl)- 1,7-naphthyridine,8-amino-2-(4-methoxyphenyl)-1,7-naphthyridine,8-amino-2-(2,3-dimethoxyphenyl)-1,7-naphthyridine,8-amino-2-(2,6-dimethoxyphenyl)-1,7-naphthyridine,8-amino-2-(3,4-methylenedioxyphenyl)-1,7-naphthyridine,8-amino-2-(2-chlorophenyl)-1,7-naphthyridine,8-amino-2-(3-chlorphenyl)-1,7-naphthyridine,8-amino-2-(4-chlorophenyl)-1,7-naphthyridine,8-amino-2-(2-trifluoromethylphenyl)-1,7-naphthyridine,8-amino-2-(3-trifluoromethylphenyl)-1,7-naphthyridine,8-amino-2-(4-trifluoromethylphenyl)-1,7-naphthyridine,8-amino-2-(α-naphthyl)-1,7-naphthyridine,8-amino-2-(β-naphthyl)-1,7-naphthyridine,8-amino-2-(2-chlorobenzyl)-1,7-naphthyridine,8-amino-2-(3-chlorobenzyl)-1,7-naphthyridine,8-amino-2-(4-chlorobenzyl)-1,7-naphthyridine,8-amino-2-(2-methylbenzyl)-1,7-naphthyridine,8-amino-2-(3-methylbenzyl)-1,7-naphthyridine,8-amino-2-(4-methylbenzyl)-1,7-naphthyridine,8-amino-2-(4-methoxybenzyl)-1,7-naphthyridine,8-amino-2-(2-thienyl)-1,7-naphthyridine,8-amino-2-(2-thienylmethyl)-1,7-naphthyridine,8-amino-2-(3-thienylmethyl)-1,7-naphthyridine,8-amino-2-(2-furyl)-1,7-naphthyridine, 8-amino-2-cyclobutyl-1,7-naphthyridine, 8-amino-2-cyclopentyl-1,7-naphthyridine,8-amino-2-cyclohexyl-1,7-naphthyridine,8-amino-2-(2-pyrimidinyl)-1,7-naphthyridine,8-amino-2-(3-pyrimidinyl)-1,7-naphthyridine,8-amino-2-(2-pyrazinyl)-1,7-naphthyridine.

Similarly, by substituting the 2-cyano-3-methylpyridine reactant withequivalent quantities of 2-cyano-3-ethylpyridine,2-cyano-3-benzylpyridine, 2-cyano-3-phenethylpyridine and bysubstantially following the foregoing reaction procedure there isproduced 8-amino-2,3-dimethyl-1,7-naphthyridine,8-amino-2-methyl-3-phenyl-1,7-naphthyridine,8-amino-2-methyl-3-benzyl-1,7-naphthyridine, respectively. Similarly, ineach of those reactions wherein the 2-cyano-3-methylpyridine has beensubstituted with another 2-cyano-3-substituted pyridine the acetonitrilereactant may also be substituted with the aforementioned nitriles and bysubstantially following the procedure described in the example, there isproduced the appropriate 8-amino-2-and 3-substituted 1,7-naphthyridine.

The compounds of this invention are useful as anti-fungal andantibacterial agents. In general, the potency of these compounds againsta variety of bacteria and fungi by standard and conventional techniquessuch as with the use of standard disc assays. In general, the compoundsare dissolved in 0.1N HCl and discs are dipped in appropriateconcentrations to provide discs containing 200 or 20 mcg./disc. Bacteriawere grown on nutrient agar, and were incubated at 37° C. for 24 hours;yeasts were grown on Sabourauds agar and were incubated at 27° C. for 48hours; Trichophyton was grown on Mycosel agar and was incubated at 27°C. for 4 days prior to measurement of inhibition zones. Typical of theresults of the anti-bacterial and anti-fungal effects of the compoundsof this invention are summarized by the results of8-amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine in Table I. Tubedilution tests, using conventional techniques, are used to determinefurther in vitro potency of the compounds of this invention. Typicalresults are represented by the date of Table II.

                  Table I                                                         ______________________________________                                        Disc Testing of 8-amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine                             Inhibition Zone in mm.                                                        8-Amino-2-(3-methyl-2-pyridyl)-                                               1,7-napthyridine                                               Organisms        200 mcg.    20 mcg.                                          ______________________________________                                        Staphlococcus aureus 209 P                                                                     40          ±                                             Streptococcus pyrogenes C                                                                      27          0                                                Escherichia coli 30          0                                                Pseudomonas aeruginosa                                                                         30          0                                                Salmonella schottmuelleri                                                                      30          ±                                             Candida albicans 404                                                                           12          0                                                Candida albicans 420                                                                           30          0                                                Candida albicans 406                                                                           0           0                                                Candida albicans 12031                                                                         0           0                                                Candida albicans 400                                                                           16          0                                                Candida albicans 402                                                                           16          0                                                Candida albicans 403                                                                           0           0                                                Candida albicans 411                                                                           ±        0                                                Saccharomyces cerevisiae                                                                       20          0                                                Trichophyton mentagrophytes                                                                    40          -                                                Bacteria on nutrient agar, yeasts on Sabourauds agar and                      Trichophyton on Mycosel agar.                                                 ______________________________________                                    

                  Table II                                                        ______________________________________                                         In Vitro Activity of 8-amino-2-(3-methyl-2-pyridyl)-1,7-                     naphthyridine by Tube Dilution                                                                 8-Amino-2-(3-methyl-2-pyridyl)-                              Organisms        1,7-naphthyridine                                            ______________________________________                                        Staphylococcus aureus 209P                                                                     25                                                           Streptococcus pyogenes C                                                                       25                                                           Escherichia coli 25                                                           Pseudomonas aeruginosa                                                                         25                                                           Candida albicans 404                                                                           50                                                           Candida albicans 420                                                                           37.5                                                         Candida albicans 406                                                                           50                                                           Candida albicans 12031                                                                         50                                                           Candida albicans 400                                                                           37.5                                                         Candida albicans 402                                                                           50                                                           Candida albicans 403                                                                           50                                                           Candida albicans 411                                                                           37.5                                                         Saccharomyces cerevisiae                                                                       37.5                                                         Trichophyton mentogrophytes                                                                    0.75                                                         Trichophyton rubrum No. 3                                                                      17.5                                                         Trichophyton rubrum 14001                                                                      17.5                                                         Trichophyton rubrum Lyons                                                                      25                                                           Bacteria in yeast beef broth, fungi in Sabourauds dextrose                    ______________________________________                                        broth.                                                                    

The compounds contemplated as falling within Formula I are basic incharacter and form acid addition salts. These salts sometimes increasesolubility and lend themselves better to formulation than do the freebases. Accordingly, the pharmaceutically acceptable acid addition saltsof the free bases are contemplated as being within the concept of itscomposition aspect. Such salts include those derived from maleic,salicylic, succinic, methyl sulfonic, tartaric, citric, hydrochloric,hydrobromic, sulfuric, phosphoric and the like, and are prepared bystandard and well-known techniques.

In their function as therapeutically useful compounds, it isadvantageous to administer the compounds to the host animal in admixturewith an acceptable pharmaceutical carrier suitable for enteral orparenteral administration, said carrier constituting a major porton ofthe admixture. Such preparations may be in such forms as, for example,tablets, capsules and suppositories, or in liquid forms, as for example,elixirs, emulsions, sprays and injectables. In the formulation ofpharmaceutical preparations there can be employed such substances whichdo not react with the active substance, as, for example, water, gelatin,lactose, starches, magnesium stearate, talc, vegetable oils, benzylalcohols, gums, polyalkylene glycols, petroleum jelly and the like.

The active ingredient of such pharmaceutical preparations is preferablypresent in the preparation in such proportions by weight that theproportion by weight of the active ingredient to be administered liesbetween 0.1% and 50%.

Representative embodiments of the formulations containing thecompositions of this invention are as follows:

    ______________________________________                                        I TABLET FORMULATIONS                                                         Enteric Coated Tablets                                                        Formula                 mg./core                                              ______________________________________                                        8-Amino-2-(3-methyl-2-pyridyl)-                                               1,7-naphthyridine       100.0                                                 Citric acid             1.0                                                   Lactose, U.S.P.         33.5                                                  Dicalcium phosphate     70.0                                                  Pluronic F-68           30.0                                                  Sodium Lauryl sulfate   15.0                                                  Polyvinylpyrrolidone    15.0                                                  Carbowax 1500           4.5                                                   Carbowax 6000           45.5                                                  3A alcohol, 50 ml./1000 cores                                                 Corn starch             30.0                                                  Dry:                                                                           Sodium Lauryl Sulfate  3.0                                                    Magnesium stearate     3.0                                                   Tablet Weight           350.0                                                 ______________________________________                                    

Procedure -- The 8-amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine ismixed with the citric acid, lactose, dicalcium phosphate, pluronic andsodium lauryl sulfate. The above mixture is screened through a No. 60screen and damp granulated with an alcoholic solution consisting ofpolyvinylpyrrolidone. Carbowax 1500 and 6000. Add additional alcohol, ifnecessary, to bring powders to a pasty mass. Add corn starch andcontinue mixing until uniform granules are formed. Pass through a No. 10screen, tray and dry in oven at 100° C. for 12-14 hours. Reduce driedgranulation through a No. 16 screen, add sodium lauryl sulfate andmagnesium sulfate, mix and compress into desired shape on a tablemachine.

Coating -- The above cores are treated with a lacquer and dusted withtalc to prevent moisture adsorption. Sub-coat layers are added to roundout the core. A sufficient number of lacquer coats are applied to makethe core enteric. Additional sub-coats and smoothing coats are appliedto completely round out and smooth the tablet. Color coats are applieduntil desired shade is obtained. After drying the coated tablets arepolished to give the tablets an even gloss.

    ______________________________________                                        II CAPSULE FORMATIONS                                                         A. Formula             Mg./Capsule                                            ______________________________________                                        8-Amino-2-(3-methyl-2-pyridyl)-                                               1,7-naphthyridine      100.0                                                  Citric acid            1.00                                                   Pluronic, F-68         40.00                                                  Sodium lauryl sulfate  20.00                                                  Lactose                238.00                                                 Magnesium stearate     1.00                                                                          400.00                                                 ______________________________________                                    

Procedure -- Mix together8-amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine, citric acid, pluronic,sodium lauryl sulfate and lactose. Pass through a No. 80 screen. Addmagnesium stearate, mix and encapsulate into the proper size 2-piecegelatin capsule.

    ______________________________________                                        B. Formula             Mg./Capsule                                            ______________________________________                                        8-Amino-2-(3-methyl-2-pyridyl)-                                               1,7-naphthyridine      100.0                                                  Dried aluminum hydroxide gel                                                                         100.0                                                  Citric acid            1.0                                                    Pluronic, F-68         50.0                                                   Sodium lauryl sulfate  25.0                                                   Lactose                222.0                                                  Magnesium stearate     2.0                                                                           500.0                                                  ______________________________________                                    

Procedure -- Mix together8-amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine, citric acid, pluronic,sodium lauryl sulfate and lactose. Pass through a No. 80 screen. Addmagnesium stearate, mix and encapsulate into the proper size 2-piecegelatin capsule adding the dried aluminum hydroxide gel to the mixturebefore screening.

    ______________________________________                                        III ORAL SUSPENSION                                                           Formula                                                                       ______________________________________                                        8-Amino-2-(3-methyl-2-pyridyl)-                                               1,7-naphthyridine    mg./5 ml  100.0                                          Veegum, Vanderbilt   "         50.0                                           Standard granulated sugar, USP                                                                     "         2500.0                                         Sorbitol solution, USP                                                                             "         1250.0                                         Sodium saccharin, NF "         50.0                                           Sodium benzoate, USP "         5.0                                            Ethanol, USP         ml        0.025                                          Menthol, USP         mg./5 ml  1.000                                          Flavor                         Q.s.                                           Purified water, USP, to make 5 ml.                                            ______________________________________                                    

Method of Manufacture -- Dissolve the sodium saccharin, sodium benzoate,standard granulated sugar and sorbitol solution in approximately 80% ofthe required amount of water. Disperse the Veegum in approximately 5% ofthe required amount of water and add the dispersion to the previouslyprepared syrup. Prepare a slurry of the8-amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine with approximately 10%of the required amount of water and pass through a suitable colloid milluntil free of grittiness. Add the milled active slurry to the batch.Dissolve the menthol and flavor in the alcohol and add the resultingsolution to the batch. Add sufficient purified water to bring the batchto total volume. Agitate until uniform.

Additionally, the compounds of this invention are useful as antiobesityagents at dosage ranges of about 10-50 m.p.k. per day. In this end-usecharacteristic the compounds have demonstrated the ability to inhibitlipogenesis in adipose tissue as determined by administration of tracerdoses or radio-glucose together with an oral glucose level to male ratsand the radioactivity in the epididymal fat pad is measured as an indexof lipid synthesis. The test compound is administered 1 hour prior tothe administration of the glucose. The active compounds decrease theradioactivity in the fat pad. Those compounds which are active in thistest procedure, i.e. have the ability to decrease epididymal fat pad andbody weights in male rats, are very useful as antiobesity agents.

Of particular interest in the class of naphthyridines of this inventionare those compounds having in their 3-position a pyridyl radical. Ofparticular interest are 8-amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine,8-amino-2-(3-methyl-4-pyridyl)-1,7-naphthyridine and8-N-methylamino-6-(3-methyl-2-pyridyl)-1,7-naphthyridine.

In their use as antiobesity agents the compounds are administered inadmixture with suitable pharmaceutical carriers such as those describedhereinabove.

We claim:
 1. Compounds of the formulae: ##STR7## and thepharmaceutically acceptable acid addition salts thereof, wherein R₁ isselected from the group consisting of lower alkyl, phenyl, benzyl,phenethyl, and pyridyl, R is selected from the group consisting ofhydrogen, lower alkyl, phenyl, benzyl, phenethyl and pyridyl. 2.Compounds of claim 1 of the structural formula: ##STR8##
 3. Compounds ofclaim 1 of the structural formula: ##STR9##
 4. Compounds of claim 1 ofthe structural formula: ##STR10##
 5. Compounds of the formula: ##STR11##wherein R₂ ' is selected from the group consisting of hydrogen, loweralkyl, phenyl, benzyl and pyridyl, and R₃ ' is selected from the groupconsisting of lower alkyl, phenyl, benzyl, phenethyl.